The Genomic Grade Assay Compared With Ki67 to Determine Risk of Distant Breast Cancer Recurrence

Michail Ignatiadis, Hatem A. Azim, Christine Desmedt, Isabelle Veys, Denis Larsimont, Roberto Salgado, Maria B. Lyng, Giuseppe Viale, Brian Leyland-Jones, Anita Giobbie-Hurder, Rosita Kammler, Patrizia Dell'Orto, Françoise Rothé, Ioanna Laïos, Henrik J. Ditzel, Meredith M. Regan, Martine Piccart, Stefan Michiels, Christos Sotiriou

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

IMPORTANCE: The Genomic Grade Index (GGI) was previously developed, evaluated on frozen tissue, and shown to be prognostic in early breast cancer. To test the GGI in formalin-fixed, paraffin-embedded breast cancer tumors, a quantitative reverse transcriptase polymerase chain reaction assay was developed and named the Genomic Grade (GG). The GG assay has the potential to increase the clinical application of the GGI, but robust demonstration of the clinical validity of the GG assay is required.

OBJECTIVE: To evaluate the prognostic ability of the GG assay to detect breast cancer recurrence compared with centrally reviewed immunohistochemical testing of Ki67 antigen proliferation.

DESIGN, SETTING, AND PARTICIPANTS: This is an internationally collaborative substudy of a large phase 3 4-arm adjuvant trial. Patients had endocrine receptor-positive, node-positive, or node-negative nonmetastatic primary breast cancer. Patients included in this study had available formalin-fixed, paraffin-embedded samples of their primary tumors and were randomized to either a 5-year tamoxifen monotherapy arm or a 5-year letrozole monotherapy arm. Associations between either GG assay results or log2-transformed Ki67 data and survival end points were evaluated using Cox regression models stratified for chemotherapy use; the 2 vs 4 arm randomization option; and endocrine therapy assignment with and without adjustment for clinicopathological parameters, including centrally reviewed histological grade, hormone receptors, and ERBB2 (formerly HER2 or HER2/neu). The likelihood ratio statistic was used to assess the added prognostic value.

INTERVENTIONS: Central evaluation and comparison, blinded for clinical information, of the GG assay, breast cancer histological grade, and Ki67.

MAIN OUTCOMES AND MEASURES: Distant recurrence-free interval (DRFI).

RESULTS: Genomic Grade assay data were obtained in 883 breast cancer samples (62%). At a median follow-up of 8.1 years, 84 (10%) had distant recurrences. Increasing GG or Ki67 were both significantly associated with lower DRFI and added independent prognostic information to the clinicopathological prognostic factors. In patients with early node-negative breast cancer who were endocrine-only treated, 38% were GG1 with a 10-year DRFI of 99% (95% CI, 97%-100%), and 18% were histological grade 1 with a 10-year DRFI of 100% (95% CI, 100%-100%). For GG equivocal patients, the 10-year DRFI was 94% (95% CI, 90%-98%), and for GG3 patients, the 10-year DRFI was 87% (95% CI, 80%-94%).

CONCLUSIONS AND RELEVANCE: Either the GG assay or centrally reviewed Ki67 significantly improves clinicopathological models to determine distant recurrence of breast cancer. Compared with the histological grade, the GG assay can identify a higher proportion of endocrine-only treated patients with very low risk of distant recurrence at 10 years.

TRIAL REGISTRATION: clinicaltrials.gov Identifiers: NCT00004205 and NCT00004205.

Original languageEnglish
Pages (from-to)217-224
Number of pages8
JournalJAMA oncology
Volume2
Issue number2
DOIs
Publication statusPublished - Feb 1 2016

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Breast Neoplasms
Recurrence
letrozole
Paraffin
Formaldehyde
Ki-67 Antigen
Tamoxifen
Random Allocation
Reverse Transcriptase Polymerase Chain Reaction
Proportional Hazards Models
Hormones
Drug Therapy
Survival
Neoplasms

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Ignatiadis, M., Azim, H. A., Desmedt, C., Veys, I., Larsimont, D., Salgado, R., ... Sotiriou, C. (2016). The Genomic Grade Assay Compared With Ki67 to Determine Risk of Distant Breast Cancer Recurrence. JAMA oncology, 2(2), 217-224. https://doi.org/10.1001/jamaoncol.2015.4377

The Genomic Grade Assay Compared With Ki67 to Determine Risk of Distant Breast Cancer Recurrence. / Ignatiadis, Michail; Azim, Hatem A.; Desmedt, Christine; Veys, Isabelle; Larsimont, Denis; Salgado, Roberto; Lyng, Maria B.; Viale, Giuseppe; Leyland-Jones, Brian; Giobbie-Hurder, Anita; Kammler, Rosita; Dell'Orto, Patrizia; Rothé, Françoise; Laïos, Ioanna; Ditzel, Henrik J.; Regan, Meredith M.; Piccart, Martine; Michiels, Stefan; Sotiriou, Christos.

In: JAMA oncology, Vol. 2, No. 2, 01.02.2016, p. 217-224.

Research output: Contribution to journalArticle

Ignatiadis, M, Azim, HA, Desmedt, C, Veys, I, Larsimont, D, Salgado, R, Lyng, MB, Viale, G, Leyland-Jones, B, Giobbie-Hurder, A, Kammler, R, Dell'Orto, P, Rothé, F, Laïos, I, Ditzel, HJ, Regan, MM, Piccart, M, Michiels, S & Sotiriou, C 2016, 'The Genomic Grade Assay Compared With Ki67 to Determine Risk of Distant Breast Cancer Recurrence', JAMA oncology, vol. 2, no. 2, pp. 217-224. https://doi.org/10.1001/jamaoncol.2015.4377
Ignatiadis, Michail ; Azim, Hatem A. ; Desmedt, Christine ; Veys, Isabelle ; Larsimont, Denis ; Salgado, Roberto ; Lyng, Maria B. ; Viale, Giuseppe ; Leyland-Jones, Brian ; Giobbie-Hurder, Anita ; Kammler, Rosita ; Dell'Orto, Patrizia ; Rothé, Françoise ; Laïos, Ioanna ; Ditzel, Henrik J. ; Regan, Meredith M. ; Piccart, Martine ; Michiels, Stefan ; Sotiriou, Christos. / The Genomic Grade Assay Compared With Ki67 to Determine Risk of Distant Breast Cancer Recurrence. In: JAMA oncology. 2016 ; Vol. 2, No. 2. pp. 217-224.
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author = "Michail Ignatiadis and Azim, {Hatem A.} and Christine Desmedt and Isabelle Veys and Denis Larsimont and Roberto Salgado and Lyng, {Maria B.} and Giuseppe Viale and Brian Leyland-Jones and Anita Giobbie-Hurder and Rosita Kammler and Patrizia Dell'Orto and Fran{\cc}oise Roth{\'e} and Ioanna La{\"i}os and Ditzel, {Henrik J.} and Regan, {Meredith M.} and Martine Piccart and Stefan Michiels and Christos Sotiriou",
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T1 - The Genomic Grade Assay Compared With Ki67 to Determine Risk of Distant Breast Cancer Recurrence

AU - Ignatiadis, Michail

AU - Azim, Hatem A.

AU - Desmedt, Christine

AU - Veys, Isabelle

AU - Larsimont, Denis

AU - Salgado, Roberto

AU - Lyng, Maria B.

AU - Viale, Giuseppe

AU - Leyland-Jones, Brian

AU - Giobbie-Hurder, Anita

AU - Kammler, Rosita

AU - Dell'Orto, Patrizia

AU - Rothé, Françoise

AU - Laïos, Ioanna

AU - Ditzel, Henrik J.

AU - Regan, Meredith M.

AU - Piccart, Martine

AU - Michiels, Stefan

AU - Sotiriou, Christos

PY - 2016/2/1

Y1 - 2016/2/1

N2 - IMPORTANCE: The Genomic Grade Index (GGI) was previously developed, evaluated on frozen tissue, and shown to be prognostic in early breast cancer. To test the GGI in formalin-fixed, paraffin-embedded breast cancer tumors, a quantitative reverse transcriptase polymerase chain reaction assay was developed and named the Genomic Grade (GG). The GG assay has the potential to increase the clinical application of the GGI, but robust demonstration of the clinical validity of the GG assay is required.OBJECTIVE: To evaluate the prognostic ability of the GG assay to detect breast cancer recurrence compared with centrally reviewed immunohistochemical testing of Ki67 antigen proliferation.DESIGN, SETTING, AND PARTICIPANTS: This is an internationally collaborative substudy of a large phase 3 4-arm adjuvant trial. Patients had endocrine receptor-positive, node-positive, or node-negative nonmetastatic primary breast cancer. Patients included in this study had available formalin-fixed, paraffin-embedded samples of their primary tumors and were randomized to either a 5-year tamoxifen monotherapy arm or a 5-year letrozole monotherapy arm. Associations between either GG assay results or log2-transformed Ki67 data and survival end points were evaluated using Cox regression models stratified for chemotherapy use; the 2 vs 4 arm randomization option; and endocrine therapy assignment with and without adjustment for clinicopathological parameters, including centrally reviewed histological grade, hormone receptors, and ERBB2 (formerly HER2 or HER2/neu). The likelihood ratio statistic was used to assess the added prognostic value.INTERVENTIONS: Central evaluation and comparison, blinded for clinical information, of the GG assay, breast cancer histological grade, and Ki67.MAIN OUTCOMES AND MEASURES: Distant recurrence-free interval (DRFI).RESULTS: Genomic Grade assay data were obtained in 883 breast cancer samples (62%). At a median follow-up of 8.1 years, 84 (10%) had distant recurrences. Increasing GG or Ki67 were both significantly associated with lower DRFI and added independent prognostic information to the clinicopathological prognostic factors. In patients with early node-negative breast cancer who were endocrine-only treated, 38% were GG1 with a 10-year DRFI of 99% (95% CI, 97%-100%), and 18% were histological grade 1 with a 10-year DRFI of 100% (95% CI, 100%-100%). For GG equivocal patients, the 10-year DRFI was 94% (95% CI, 90%-98%), and for GG3 patients, the 10-year DRFI was 87% (95% CI, 80%-94%).CONCLUSIONS AND RELEVANCE: Either the GG assay or centrally reviewed Ki67 significantly improves clinicopathological models to determine distant recurrence of breast cancer. Compared with the histological grade, the GG assay can identify a higher proportion of endocrine-only treated patients with very low risk of distant recurrence at 10 years.TRIAL REGISTRATION: clinicaltrials.gov Identifiers: NCT00004205 and NCT00004205.

AB - IMPORTANCE: The Genomic Grade Index (GGI) was previously developed, evaluated on frozen tissue, and shown to be prognostic in early breast cancer. To test the GGI in formalin-fixed, paraffin-embedded breast cancer tumors, a quantitative reverse transcriptase polymerase chain reaction assay was developed and named the Genomic Grade (GG). The GG assay has the potential to increase the clinical application of the GGI, but robust demonstration of the clinical validity of the GG assay is required.OBJECTIVE: To evaluate the prognostic ability of the GG assay to detect breast cancer recurrence compared with centrally reviewed immunohistochemical testing of Ki67 antigen proliferation.DESIGN, SETTING, AND PARTICIPANTS: This is an internationally collaborative substudy of a large phase 3 4-arm adjuvant trial. Patients had endocrine receptor-positive, node-positive, or node-negative nonmetastatic primary breast cancer. Patients included in this study had available formalin-fixed, paraffin-embedded samples of their primary tumors and were randomized to either a 5-year tamoxifen monotherapy arm or a 5-year letrozole monotherapy arm. Associations between either GG assay results or log2-transformed Ki67 data and survival end points were evaluated using Cox regression models stratified for chemotherapy use; the 2 vs 4 arm randomization option; and endocrine therapy assignment with and without adjustment for clinicopathological parameters, including centrally reviewed histological grade, hormone receptors, and ERBB2 (formerly HER2 or HER2/neu). The likelihood ratio statistic was used to assess the added prognostic value.INTERVENTIONS: Central evaluation and comparison, blinded for clinical information, of the GG assay, breast cancer histological grade, and Ki67.MAIN OUTCOMES AND MEASURES: Distant recurrence-free interval (DRFI).RESULTS: Genomic Grade assay data were obtained in 883 breast cancer samples (62%). At a median follow-up of 8.1 years, 84 (10%) had distant recurrences. Increasing GG or Ki67 were both significantly associated with lower DRFI and added independent prognostic information to the clinicopathological prognostic factors. In patients with early node-negative breast cancer who were endocrine-only treated, 38% were GG1 with a 10-year DRFI of 99% (95% CI, 97%-100%), and 18% were histological grade 1 with a 10-year DRFI of 100% (95% CI, 100%-100%). For GG equivocal patients, the 10-year DRFI was 94% (95% CI, 90%-98%), and for GG3 patients, the 10-year DRFI was 87% (95% CI, 80%-94%).CONCLUSIONS AND RELEVANCE: Either the GG assay or centrally reviewed Ki67 significantly improves clinicopathological models to determine distant recurrence of breast cancer. Compared with the histological grade, the GG assay can identify a higher proportion of endocrine-only treated patients with very low risk of distant recurrence at 10 years.TRIAL REGISTRATION: clinicaltrials.gov Identifiers: NCT00004205 and NCT00004205.

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